Overview1
RAGNAR (NCT04083976) is a phase 2, open-label, single-arm, global, multicenter study evaluating the efficacy and safety of BALVERSA in adult and pediatric patients (children aged ≥6 years) with unresectable, locally advanced, or metastatic solid tumor malignancies (tumor agnostic), FGFR mutations or fusions, and documented disease progression.
RAGNAR is an ongoing study that is currently not recruiting.
Key Eligibility Criteria1,2
- Age ≥6 years.
- Histologically confirmed, unresectable, locally advanced or metastatic solid tumor with FGFR mutation/gene fusion.
- Patient must have received ≥1 prior line of systemic therapy for metastatic disease or must be a child/adolescent with a newly diagnosed solid tumor and no acceptable standard therapies.
- Documented disease progression (any progression requiring a change in treatment prior to full-study screening).
Study Design1-3
Screening Phase
Molecular eligibility and
full-study screening
Treatment Phase
BALVERSA oral tablet
(Planned N=336)
End of Treatment Visit
Occurs 30 days after the last
BALVERSA dose
Follow-up Phase
Follow-up until death, consent withdrawal,
loss to follow-up, or
end of study
Molecular Screening4
- Preliminary results of molecular screening for FGFR alterations in
110 patients were reported.
- CCA was the most common malignancy (n=30; 27%). Overall, 80% of patients with CCA had FGFR2 fusion, with the most common FGFR variant being FGFR2-BICC1.
- High-grade glioma was the second most common malignancy (n=21; 19%). Overall, 95% of patients with high-grade glioma had FGFR3 fusion, with the most common FGFR variant being FGFR3-TACC3.
Efficacy Results2,5-12
- After a median follow-up of 17.9 months, in the primary cohort of patients with 16 solid tumor types (n=217)2,5:
- ORR per IRC: 30% (95% CI, 24-36)
- Investigator-assessed ORR: 25% (95% CI, 20-32)
- DCR: 74% (95% CI, 67-80)
- Median DOR: 6.9 months (95% CI, 4.4-7.1)
- Investigator-assessed median DOR: 7 months (95% CI, 5.5-8.5)
- CBR: 46% (95% CI, 39-53)
- Median PFS: 4.2 months (95% CI, 4.1-5.5)
- Median OS: 10.7 months (95% CI, 8.7-12.1)
- Additional efficacy results for other patient populations have been presented and/or published.6-12
Safety Results2,5-12
- After a median follow-up of 17.9 months, in the primary cohort of patients with 16 solid tumor types (n=217)2,5:
- Grade ≥3 TEAEs: 46%
- Most common grade ≥3 BALVERSA related TEAEs: stomatitis (12%), palmar-plantar erythrodysesthesia syndrome (6%), and hyperphosphatemia (5%)
- Most common serious TRAEs (grade ≥3) were stomatitis (2%) and diarrhea (1%).
- Serious TEAEs: 39%
- Most common serious grade ≥3 TRAEs: stomatitis (2%) and diarrhea (1%)
- Most common TRAEs that led to treatment discontinuation: palmar-plantar erythrodysesthesia syndrome (2%) and stomatitis (2%)
- Central serous retinopathy events: 14%
- Treatment-related deaths: none
- Additional safety results for other patient populations have been presented and/or published.6-12
Note: CBR, clinical benefit rate; CCA, cholangiocarcinoma; CI, confidence interval; DCR, disease control rate; DOR, duration of response; FGFR, fibroblast growth factor receptor; IRC, independent review committee; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TEAE, treatment-emergent adverse event; TRAE, treatment-emergent adverse event.
RAGNAR (NCT04083976) is a phase 2, open-label, single-arm, global, multicenter study evaluating the efficacy and safety of BALVERSA in adult and pediatric patients (children aged ≥6 years) with unresectable, locally advanced, or metastatic solid tumor malignancies (tumor agnostic), FGFR mutations or fusions, and documented disease progression.1
RAGNAR is an ongoing study that is currently not recruiting.1
RAGNAR Study Design1-3
Key Inclusion Criteria
- Age ≥6 years.
- Histologically confirmed, unresectable, locally advanced or metastatic solid tumor with FGFR mutation/gene fusion.
- Patient must have received ≥1 prior line of systemic therapy for metastatic disease or must be a child/adolescent with a newly diagnosed solid tumor and no acceptable standard therapies.
- Documented disease progression (any progression requiring a change in treatment prior to full‑study screening).
Key Exclusion Criteria
- Prior chemotherapy, targeted therapy, or treatment with an investigational anticancer agent <30 days or ≤5 drug half-lives (whichever is longer) before the first dose of BALVERSA.
- Presence of FGFR gatekeeper and resistance mutations.
- Histologically confirmed transitional cell carcinoma of the urothelium (ie, bladder cancer) or hematologic malignancy (ie, myeloid and lymphoid neoplasms).
- Active malignancies other than for disease requiring therapy.
- For patients with NSCLC only: pathogenic somatic mutations or gene fusions in EGFR, ALK, ROS1, NTRK, and BRAF V600E.
Screening Phase
Molecular eligibility and full-study screening
Treatment Phase
BALVERSAa oral tablet
Planned N=336
End of Treatment Visit
Occurs 30 days after the last dose of BALVERSA
Follow-up Phase
Follow-up until death, consent withdrawal, loss to follow-up, or end of study
Primary Endpoint
- ORR per IRC, independent review committee, assessed by CT or MRI per RECIST v1.1 or RANO criteria
Secondary Endpoints
- Investigator-assessed ORR
- Safety
- DCR
- DOR
- PFS
- PK
- CBR
- OS
- HRQoL
aTreatment until disease progression, intolerable toxicity, consent withdrawal, or investigator’s decision to discontinue treatment.
Please visit ClinicalTrials.gov for complete study details.
Primary Endpoint1
- ORR per IRC
Secondary Endpoints2
- Investigator-assessed ORR
- DOR
- DCR
- CBR
- PFS
- OS
- Safety
- HRQoL
- PK
Primary Analysis Methods2
- The primary cohort included patients of age ≥12 years with unresectable, locally
advanced, or metastatic solid tumors (except urothelial carcinoma), predefined FGFR1-4
alterations (mutations/fusions), and documented disease progression. Patients had ≥1
prior line of systemic therapy and no alternative standard therapy. Patients received
BALVERSA PO once daily on a 21-day cycle until disease progression or intolerable toxicity.
- Adult and adolescent patients (aged ≥15 to <18 years) were initiated with BALVERSA 8 mg with possible uptitration to 9 mg based on cycle 1 day 14 serum phosphate levels.
- Adolescent patients (aged ≥12 to <15 years) were initiated with BALVERSA 5 mg with possible uptitration to 6 mg or further to 8 mg based on cycle 1 day 14 and cycle 2 day 7 serum phosphate levels.
- Efficacy for patients with non-CNS tumors was assessed using RECIST v1.1 by CT or MRI of the chest, abdomen, and pelvis every 6 weeks for 12 months, and every 12 weeks thereafter.
- Efficacy for patients with primary brain tumors was assessed using RANO by brain MRI at baseline, every 6 weeks for the first 12 months, and every 12 weeks thereafter.
RAGNAR Primary Analysis: Baseline Demographics and Disease Characteristics2
| Characteristic | N=217 |
|---|---|
| Age, median (range), years | 57 (48-64) |
| Sex | |
| Male | 120 (55) |
| Female | 97 (45) |
| Region | |
| Europe | 94 (43) |
| Asia | 53 (24) |
| North America | 48 (22) |
| Rest of world | 22 (10) |
| Race | |
| White | 112 (52) |
| Asian | 57 (26) |
| Black or African American | 6 (3) |
| Other or not reported | 42 (19) |
| ECOG PS (n=215)a | |
| 0 | 65 (30) |
| 1 | 149 (69) |
| 2b | 1 (<1) |
| Time from progression/relapse on the last line of treatment to first dose, months (n=214)c | 1.25 (0.82-2.14) |
| Metastatic sites | |
| Presence of metastases sites | 179 (82) |
| Lymph node | 119 (55) |
| Liver | 99 (46) |
| Lung | 94 (43) |
| Bone | 49 (23) |
| Adrenal gland | 17 (8) |
| Brain | 12 (6) |
| Spinal cord | 5 (2) |
| Other | 68 (31) |
|
Data are presented as n (%) unless otherwise specified. aECOG PS is only applicable to adults. bOne patient was enrolled with an ECOG PS score of 2, which did not meet protocol eligibility criteria. cApplicable only to patients with nonmissing values for progression/relapse date of last line of treatment. |
|
- Preliminary results of molecular screening for FGFR alterations in 110 patients were reported.4
RAGNAR Molecular Screening for FGFR Alterations4
| Malignancy | n (%) | Predominant Eligible FGFR Alteration (%) |
Most Frequent FGFR Variant(s) |
|---|---|---|---|
| CCA | 30 (27) | FGFR2 fusion (80) | FGFR2-BICC1 fusion |
| Glioma, high-grade | 21 (19) | FGFR3 fusion (95) | FGFR3-TACC3 fusion |
| Pancreatic | 9 (8) | FGFR2 fusion (78) | FGFR1 and FGFR2 fusions |
| NSCLC | 8 (7) | FGFR3 fusion (63) | FGFR3-TACC3 fusion |
| Breast | 5 (5) | FGFR2 mutation (40) and fusion (40) | FGFR1 and FGFR2 mutations/fusions |
| Colorectal | 5 (5) | FGFR3 mutation (40) and fusion (40) | FGFR3-TACC3 fusion |
| Endometrial | 4 (4) | FGFR2 mutation (100) | FGFR2-C382R mutation |
| Gastric | 4 (4) | FGFR3 mutation (50) | FGFR3 mutations |
| Ovarian | 4 (4) | FGFR2 fusion (50) | FGFR1-3 mutations/fusions |
| Cancer of unknown primary | 4 (4) | FGFR2 fusion (50) | FGFR2 and FGFR3 mutations/fusions |
| Cervical | 3 (3) | FGFR3 mutation (100) | FGFR3-S249C mutation |
| Head and neck, squamous cell | 3 (3) | FGFR3 fusion (67) | FGFR3-TACC3 fusion |
| Esophageal | 2 (2) | FGFR3 mutation (50) and fusion (50) | FGFR3 mutations/fusions |
| Glioma, low-grade | 2 (2) | FGFR1 mutation (100) | FGFR1-K656E mutation |
| Prostate | 2 (2) | FGFR3 mutation (50) and fusion (50) | FGFR3 mutations/fusions |
| Salivary gland | 2 (2) | FGFR2 mutation (50) | FGFR1 and FGFR2 mutations/fusions |
| Basal cell | 1 (1) | FGFR2 mutation (100) | FGFR2 mutation |
| Thymic | 1 (1) | FGFR1 fusion (100) | FGFR1 fusion |
- The median follow-up for efficacy was 17.9 months (IQR, 13.6-23.9), median treatment
duration was 4.3 months (IQR, 2.1-9.2), and ORR per IRC assessment
was 64 (30%; 95% CI, 24-36) of 217 patients.2
- Responses were observed in 16 distinct tumor types. No responses were observed for cervical cancer, soft-tissue sarcoma, and prostate cancer. Other tumor types with response included duodenal cancer and thyroid carcinoma.
- Among the 64 responding patients, 6 (3%) had a CR and 58 (27%) had a PR.
- ORR was 25% (95% CI, 16-37) in patients with FGFR 1-3 mutations and 33% (95% CI, 25-41) in patients with FGFR 1-3 fusions.
- Median time to response was 1.4 months (IQR, 1.4-2.7) after initiation of BALVERSA treatment.2
- Investigator-assessed ORR was 25% (95% CI, 20-32), median DOR was 6.9 (95% CI, 4.4-7.1) months (investigator-assessed median DOR was 7 [95% CI, 5.5-8.5] months), DCR was 74% (95% CI, 67-80), CBR was 46% (95% CI, 39-53), median PFS was 4.2 (95% CI, 4.1-5.5) months (there were 160 PFS events), and median OS was 10.7 (95% CI, 8.7-12.1) months.2
RAGNAR Primary Cohort Analysis: Confirmed Response Rates by Tumor Type2,5
| Tumor Type | N (Treated) | ORR (%) | DCR (%) |
|---|---|---|---|
| Total | 217 | 30 | 74 |
| Salivary | 5 | 100 | 100 |
| Pancreatic | 18 | 56 | 94 |
| CCA | 31 | 52 | 97 |
| Endometrial | 8 | 50 | 75 |
| Non-squamous NSCLC | 9 | 33 | 56 |
| Squamous head and neck | 15 | 33 | 87 |
| Breast | 16 | 31 | 69 |
| Low-grade glioma | 7 | 29 | 71 |
| Cancer of unknown primary | 8 | 25 | 88 |
| Ovarian | 8 | 25 | 63 |
| Squamous NSCLC | 14 | 21 | 86 |
| Othera | 13 | 15 | 77 |
| Gastric | 8 | 13 | 63 |
| Esophageal | 8 | 13 | 38 |
| High-grade glioma | 30 | 10 | 57 |
| aDuodenal cancer and thyroid carcinoma (n=1 confirmed ORR, each). | |||
- At a median treatment exposure of 4.3 (IQR, 2.1-9.2) months, 216 (99.5%) patients experienced ≥1 TEAEs.2
- BALVERSA-related grade ≥3 TEAEs occurred in 100 (46%) patients.2
- The most frequent BALVERSA-related grade ≥3 TEAEs were stomatitis (12%), palmar-plantar erythrodysesthesia (6%), and hyperphosphatemia (5%).
- Serious TEAEs occurred in 85 (39%) patients. The most common serious grade ≥3 TRAEs were stomatitis in 4 (2%) patients and diarrhea in 2 (1%) patients. The most common TRAEs that led to treatment discontinuation were palmar-plantar erythrodysesthesia syndrome in 3 (2%) patients and stomatitis in 3 (2%) patients.2
- Central serous retinopathy events occurred in 31 (14%) patients.2
- Grade 1-2: Chorioretinopathy occurred in 8 (4%) patients, detachment of retinal pigment epithelium in 7 (3%) patients, and retinal detachment in 6 (3%) patients.
- Grade 3: Retinal edema (<1%).
- TEAEs led to death in 8 (4%) patients (multiple organ dysfunction syndrome, pyrexia, COVID-19, sepsis, pulmonary embolism, respiratory failure, cardiac arrest, and subdural hematoma); all were considered unrelated to BALVERSA by investigator assessment.2
RAGNAR Primary Cohort Analysis: TEAEs by Grade (≥20% in Any Grade Group)2
| TEAEs by Worst Toxicity Grade (≥20% in Any Grade Group), n (%) |
N=217 | |||
|---|---|---|---|---|
| Grade 1-2 | Grade 3 | Grade 4 | Grade 5 | |
| All TEAEs | 64 (29) | 124 (57) | 20 (9) | 8 (4) |
| Hyperphosphatemia | 143 (66) | 11 (5) | 0 | 0 |
| Diarrhea | 119 (55) | 9 (4) | 0 | 0 |
| Stomatitis | 95 (44) | 25 (12) | 0 | 0 |
| Dry mouth | 105 (48) | 1 (<1) | 0 | 0 |
| Dry skin | 73 (34) | 4 (2) | 0 | 0 |
| Palmar-plantar erythrodysesthesia syndrome | 61 (28) | 12 (6) | 0 | 0 |
| Constipation | 64 (29) | 2 (1) | 0 | 0 |
| Fatigue | 56 (26) | 7 (3) | 0 | 0 |
| Alanine aminotransferase increased | 51 (24) | 11 (5) | 0 | 0 |
| Aspartate aminotransferase increased | 53 (24) | 5 (2) | 0 | 0 |
| Decreased appetite | 55 (25) | 3 (1) | 0 | 0 |
| Anemia | 39 (18) | 18 (8) | 0 | 0 |
| Dry eye | 48 (22) | 0 | 0 | 0 |
| Alopecia | 44 (20) | 0 | 0 | 0 |
| CBR | Clinical benefit rate | IQR | Interquartile range |
|---|---|---|---|
| CCA | Cholangiocarcinoma | MRI | Magnetic resonance imaging |
| CI | Confidence interval | NSCLC | Non-small cell lung cancer |
| CNS | Central nervous system | ORR | Objective response rate |
| COVID-19 | Coronavirus disease 2019 | OS | Overall survival |
| CR | Complete response | PFS | Progression-free survival |
| CT | Computed tomography | PK | Pharmacokinetics |
| DCR | Disease control rate | PO | Orally |
| DOR | Duration of response | PR | Partial response |
| ECOG PS | Eastern Cooperative Oncology Group performance status | RANO | Response Assessment in Neuro-Oncology |
| FGFR | Fibroblast growth factor receptor | RECIST | Response Evaluation Criteria in Solid Tumours |
| HRQoL | Health-related quality of life | TEAE | Treatment-emergent adverse event |
| IRC | Independent review committee | TRAE | Treatment-related adverse event |
A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 27 May 2024.
- Janssen Research & Development LLC. A study of erdafitinib in participants with advanced solid tumors and fibroblast growth factor receptor (FGFR) gene alterations. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2024 May 27]. Available from: https://clinicaltrials.gov/study/NCT04083976 NLM Identifier: NCT04083976.
- Pant S, Schuler M, Iyer G, et al. Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study. Lancet Oncol. 2023;24(8):925-935.
- Schuler M, Tabernero J, Massard C, et al. Phase 2 open-label study of erdafitinib in adult and adolescent patients with advanced solid tumors harboring fibroblast growth factor receptor gene alterations. Poster presented at: European Society of Medical Oncology (ESMO) Congress; September 18-22, 2020; Virtual.
- Massard C, Pant S, Iyer G, et al. Preliminary results of molecular screening for FGFR alterations in the RAGNAR histology-agnostic study with the FGFR inhibitor (FGFRi) erdafitinib. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 4-8, 2021; Virtual.
- Pant S, Schuler M, Iyer G. Efficacy and safety of erdafitinib in adults with cholangiocarcinoma (CCA) with prespecified fibroblast growth factor receptor alterations (FGFRalt) in the phase 2 open-label, single-arm RAGNAR trial: expansion cohort results. Poster presented at: American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium; January 19-21, 2023; San Francisco, CA and Virtual.
- Pant S, Schuler M, Iyer G, et al. Tumor agnostic efficacy and safety of erdafitinib (erda) in patients (pts) with advanced solid tumors with prespecified FGFR alterations (FGFRalt): RAGNAR primary analysis. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 2-6, 2023; Chicago, IL and Virtual.
- Pant S, Arnold D, Tabernero J, et al. Efficacy and safety of erdafitinib in adults with pancreatic cancer and prespecified fibroblast growth factor receptor alterations (FGFRalt) in the phase 2 open-label, single-arm RAGNAR trial. Poster presented at: European Society of Medical Oncology (ESMO) Congress; October 20-24, 2023; Madrid, Spain.
- Carranza O, Schuler M, Tabernero J, et al. Efficacy and safety of erdafitinib in adults with breast cancer and prespecified fibroblast growth factor receptor alterations in the phase 2 open-label, single-arm RAGNAR trial. Poster presented at: American Society for Clinical Oncology (ASCO) Congress; May 31-June 4, 2024; Chicago, IL.
- Lugowska I, Schuler M, Loriot Y, et al. Efficacy of erdafitinib in adults with advanced solid tumors and non-prespecified fibroblast growth factor receptor mutations in the phase 2 RAGNAR trial: exploratory cohort. Poster presented at: American Society for Clinical Oncology (ASCO) Congress; May 31-June 4, 2024; Chicago, IL.
- Witt O, Sait SF, Diez B, et al. Efficacy and safety of erdafitinib in pediatric patients with advanced solid tumors and FGFR alterations in the phase 2 RAGNAR trial. Oral Presentation at: American Society for Clinical Oncology (ASCO) Congress; May 31-June 4, 2024; Chicago, IL.
- Schuler M, Tabernero J, Carranza O, et al. Efficacy and safety of erdafitinib in adults with NSCLC and prespecified fibroblast growth factor receptor alterations in the phase 2 open-label, single-arm RAGNAR trial. Oral Presentation at: American Society for Clinical Oncology (ASCO) Congress; May 31-June 4, 2024; Chicago, IL.
- Pant S, Park JO, Su W-C, et al. Efficacy and safety of erdafitinib in patients with advanced or metastatic cholangiocarcinoma and FGFR alterations: pooled analysis of RAGNAR and LUC2001 studies. Poster presented at: American Society for Clinical Oncology (ASCO) Congress; May 31-June 4, 2024; Chicago, IL.